Hail the Tattletale

Off-label drug use generally involves prescribing currently available and marketed medications for an indication that has never received regulatory approval. Healthcare professionals may be motivated to prescribe a drug off-label for a number of legitimate reasons – and regulatory bodies such as the FDA do not limit or control how medications are prescribed. However, promoting medications for off-label use is illegal, and has led to several large settlements for illegal marketing by pharmaceutical companies.

There is a growing body of scientific literature on the deceptive marketing practices used by some dishonest pharmaceutical companies, and the potentially highly negative impact that this has on patient health. One of the most commonly cited instances of hazardous off-label promotion is the marketing of antipsychotics, such as Risperdal, to control behavioral symptoms in elderly patients with dementia, a use that is not only accepted as generally ineffective but that also has been shown to increases the risk of death by over 60 percent. Another example is Paxil, an antidepressant, promoted off label for use in children and adolescents with depression, despite evidence of increased suicidality in this group following drug treatment (1).

However, most of the literature on illegal marketing is US based and much less is known about off-label promotion in other countries. My collaborators and I decided to look at illegal marketing in the UK, and to compare this with the situation in the US. Both the US and UK are very important drug markets with influential regulatory systems, but there has been little consideration of the extent to which current institutional arrangements for regulating off-label promotion in the UK are effective in detecting, deterring, and sanctioning off-label promotion compared with the most commonly pursued enforcement strategies in the US.

In the US, extensive examination of company documents and witnesses over the course of Department of Justice and congressional investigations into corporate illicit behaviors has provided extraordinary insight into two aspects. First, the complex range of off-label marketing practices that companies engage in and, second, the coordinated and planned nature of illegal marketing campaigns. Such practices include companies paying speaker fees to doctors to influence prescribing; using the sales force to promote off-label uses; directing physician workshops and dinners focused on off-label uses; paying doctors to attend “advisory boards” promoting off-label uses; and creating a purportedly independent online education organization to stimulate off-label use.

In our recent paper, we show that in the majority of cases where companies in the UK were caught promoting drugs off-label, they had promoted drugs in print material – typically via a print advertisement (2). We identified 74 cases of verified off-label promotion in the UK over a ten-year period, which is a considerable number of cases, but unlikely to be indicative of the true prevalence of off-label promotion. Our data from the UK does not show any particular trend in reported off label promotion breaches; off-label promotion rulings peaked in 2003 and 2009, but it is not possible to demonstrate trends in actual prevalence. Similarly, although the number of whistle-blower settlements in the US – including for off label promotion – has been consistently increasing since 2002, it is not known if this is because off label marketing activities are increasing, or if whistle-blowers and the Department of Justice are being more proactive – or both.

One plausible explanation for the differences in the scope and complexity of uncovered off-label practices in the UK and US is that the US legal and regulatory environment may be more effective at detecting and interrogating off-label promotion than the UK’s self-regulatory system; the US system appears to provide far greater insight into the nature and extent of illegal corporate activity. Specifically, the UK self-regulatory system for exposing marketing violations relies largely on complaints from company outsiders – rather than the US system – which may explain why most off-label promotion rulings in the UK relate to plainly visible promotional activities, such as advertising. Could there be more covert activities taking place also? More research in this area would be beneficial. 

Honesty is the best policy

The FDA is responsible for regulating drug marketing in the US, including off-label promotion. But in addition, federal and state prosecutors – and private citizens – can initiate enforcement actions against companies for violations of criminal and civil laws. Prosecutions at the federal level are led by the Department of Justice and, in recent years, the majority of US federal prosecutions of pharmaceutical companies for off-label promotion have rested on whistle-blower-initiated actions under the False Claims Act. From January 2009 through September 2012, the US Department of Justice recovered nearly $10.5 billion in whistle-blower suits under the False Claims Act. Importantly, the False Claims Act offers a major financial incentive for whistle-blowers that help uncover illegal activity; they are usually awarded around 15-25 percent of any recovered damages, which could equate to tens or hundreds of millions of dollars. In the UK, the Medicines & Healthcare products Regulatory Agency (MHRA) is responsible for regulating drug marketing, including off-label promotion, but – unlike the FDA – it has delegated an important part of this responsibility to an industry self-regulatory authority: the Prescription Medicines Code of Practice Authority (PMCPA). In the UK, there is no “False Claims Act” and no US-style governmental investigations. Instead, the self-regulatory system for detecting violations relies heavily on complaints from external parties. Furthermore, the PMCPA is not an investigative body; its rulings are based on each party’s submissions, and the burden is on the complainant to show, on the balance of probabilities, that a breach of the Association of the British Pharmaceutical Industry (ABPI) Code of Practice has occurred. Cases are determined relatively quickly, and the PMCPA will impose an administrative fine for breaches, but not for violation of relevant UK or EU laws. Whilst the speed with which the PMCPA is able to administer cases and reach decisions is a positive feature of the self-regulatory system, the PMCPA lacks the investigative powers to discover the kind of carefully orchestrated company campaigns that Department of Justice investigations have revealed. The administrative charges on violating companies in the UK are typically £3,500, which is unlikely to concern most pharmaceutical companies. The administrative charges collected by the PMCPA are used to finance self-regulation, and they do not reflect the seriousness of company breaches (nor are they designed to harm corporations financially). In fact, charges for violations are typically less than a company would pay for a single print advertisement; hardly sufficient to serve as any kind of deterrent function!

In light of all this, the UK’s Medicines and Healthcare Products Regulatory Agency and the PMCPA need to strengthen their regulatory oversight by demanding that companies submit all post-publication promotional material for review. To increase the transparency and accountability of regulatory oversight, the submitted promotional material should be publicly available upon request.

Also, the capacity of the regulatory bodies needs to be strengthened to uncover relatively complex and hidden off-label promotional practices. The UK Government should increase incentives and protections for whistle-blowers and encourage US-style investigation of allegations. The fact that infringing corporations pay charges aimed at keeping the self-regulatory system afloat, rather than providing compensation for damages caused by – and profits generated as a result of – illicit promotion represents a major weakness in the UK system.

Finally, since much off-label promotion in the UK appears directed at prescribers, the buck often stops with healthcare professionals. It is imperative that physicians are attentive to – and increasingly report – instances of off-label promotion.

But although our study looked at the UK, what about other markets? Perhaps other regions could learn from the US system too. I encourage more research to be conducted in this area and for the regulators in all countries to look more closely at off-label marketing.